Brain

Which neurotransmitter plays a key role in OCD

The brain is awash with neurotransmitters.  Knowing which type of neurotransmitter does what and where is a pretty important thing to know.  For OCD one of the key functional circuits of the brain is the cortico-striatal-thalamo-cortical (CSTC).  Like the London underground the brain has really intensively functioning units that are like stations that are joined by communication tunnels.  There is not one spot in the brain solely responsible for OCD symptoms.

In this interconnected circuit there are functional areas that seem to influence symptoms more than others.  One of these is the anterior cingulate cortex (ACC – shown below).  The bit that is of most interest is the part towards the nose/front.  This is called the rostral anterior cingulate cortex (rACC).

 

The neurotransmitters in this area that are of interest are glutamine and glutamate.  Like twins who dress alike they are hard to distinguish when using older brain scanning technology.  There is now a new brain scanning technique that will separate the goats from the sheep.  In this case it is the glutamine for glutimate.  The gizmo shown below does the standard functional magnetic resonance imaging (fMRI) plus the newer analysis of proton magnetic resonance spectroscopy (H-MRS).

A recent study in 2015 examined glutamine and glutamate.  The researchers had made three predictions; One: people with OCD would have increased rostral anterior cingulate cortex (rACC) activation during activities that invoke OCD symptoms compared with the non-OCD group.  Two: People with OCD would demonstrate an elevated Gln/Glu ratio compared to people without OCD; and three: rACC activation and Gln/Glu ratio would show some kind of relationship.

The results showed that rACC did activate during the ‘OCD task’ but the glutamatergic neurotransmitters did not appear to be responsible for the rACC dysfunction.  Put simply the researchers could point the finger at what area seems to cause the problem but not the exact mechanism of how it achieved.

 

Reference:

Brennan, B.P., Tkachenko, O., Schwab, Z.J., Juelich, R.J., Ryan, E.M., Athey, A.J., Pope, H.G., Jenike, M.A., Baker, J.T., Killgore, W.D., Hudson, J.I., Jensen, J.E., & Rauch, S.L. (2015). An Examination of Rostral Anterior Cingulate Cortex Function and Neurochemistry in Obsessive–Compulsive Disorder. Neuropsychopharmacology, 40, 1866-1876.

Image attributions:

CC BY-SA 2.1 jp, https://commons.wikimedia.org/w/index.php?curid=12565716

flickr.com/photos/11304375@N07/3081315619

Deep brain stimulation and OCD

We will be talking about deep brain stimulation (DBS) for OCD but lets take a brief diversion first.  If you were ever a medical history buff you may have heard of trepanation,   From the image below you can see that involves making a hole in the skull.

Trepanation

At first pass you would not think that making a hole in a patients skull would be the ideal remedy for medical issues such as seizures, migraines and mental disorders.  It is a fairly invasive medical strategy that fortunately did not always lead to the death of the patient.

The picture above by Hieronymus Bosch shows the technique applied in the middle ages.  Fortunately today’s doctors have taken this hit and miss technique and applied it in a straight forward way to address the buildup of intracranial pressure (pressure in the skull).  The image below shows a modern medical device to address intracranial pressure.  The is an old and brutal technique of trepanation has been updated to work relatively safely to address significant medical problems.

 

Let us now jump to electroconvulsive therapy, best known as ECT and made famous in the movie “One flew over the cuckoo’s nest”.  The medical technique of applying a strong electrical shock to the brain seemed to help with depressive patients.  Electrodes were placed at one or either side of the head and a significant electric charge was applied to the brain.  When ECT was first introduced it was a hit and miss affair that sometimes left the patient with significant memory problems.

The technique has been refined and the horrible consequences of older style ECT therapy have been substantially reduced, although some memory loss is common even with modern approaches.  Once again it is an old technique refined to work relatively safely to address significant medical problems.

Deep Brain Stimulation

Relatively recently a variant on the ECT technique has been developed called deep brain stimulation.  ECT placed the electrodes on the outside and deep brain stimulation places tiny electrodes on the inside. Electrodes are inserted into target areas of the brain and small pulses of electrical stimulation are applied.  The stimulation may increase the output of a region of neurons or activate inhibition circuits.  The placement of the electrodes determines what functionality is increased or decreased.  Like ECT the precise mechanisms of how deep brain stimulationworks is not fully understood but early observations using special microscopes shows the following:

  • Inhibits the actions of functional elements of the brain through the release of neurotransmitters (GABA and Adenosine).
  • Can excite other parts of the brain via axons and glutamate
  • Changes the firing patterns of regions of the brain (much like a pacemaker in a heart)
  • Grows dentate gyrus cells and make better connections to the hippocampus

With a pacemaker there is a fairly clear stimulation point that helps define the beat of the heart.  Applying a regular electrical pulse at this specific point pretty much controls the whole game.  For depression and OCD there is not a single point in the brain that can be fixed.  Brain function is dispersed and its outcomes are achieved via complex web of controls.  Some areas of the brain need to be inhibited and some need to be excited at just the right amounts.

At this point deep brain stimulation has been shown promising results for depression.  If the complex neuro-mechanisms controlling OCD are worked out then in principle stimulation and inhibition to these functional areas could improve OCD symptoms.  At this point deep brain stimulation is an inexact science.  Regions of the brain that usually do one thing can lead to another result in another person.  This makes sense when you consider the brain is not made up like a fixed road map.  Each area of the brain is woven together with hundreds of thousands of unique connections – each individual connection  influences the outcome of the connected region in its own special way.  In years to come we will likely see the micro electrode inserted into the brain as the equivalent of electronic sledgehammers stimulating vast clumps of neurons that trigger a range of activities not unlike the scattering of billiard balls at the start of a pool game.  The fact that the right balls drop into the pockets often enough is why deep brain stimulation is currently seen a future hope. In time it is hoped that it can be refined to deliver more consistent and tailored interventions.

Deep Brain Stimulation summary for OCD

The functional system for OCD treatment lies predominately in the cortico-striato-thalamocortical circuit.  The two key targets are ACC (anterior cingulate cortex) and OFC (orbitofrontalcortex).  The authors conclude that for treatment resistant OCD deep brain stimulation is an effective option.

 

Journal attribution:

Bourne, S. K., Eckhardt, C. A., Sheth, S. A., & Eskandar, E. N. (2012). Mechanisms of deep brain stimulation for obsessive compulsive disorder: effects upon cells and circuits. Frontiers in Integrative Neuroscience6, 29. http://doi.org/10.3389/fnint.2012.00029

 

Image attributions:

By Rama, CC BY-SA 3.0 fr, https://commons.wikimedia.org/w/index.php?curid=58036467

By Rodw – Own work, CC BY-SA 4.0, https://commons.wikimedia.org/w/index.php?curid=34135969

http://www.medtronic.com/us-en/healthcare-professionals/therapies-procedures/neurological/shunting-hydrocephalus.html

 

Attention switching linked to OCD, ASD and ADHD

Imagine a long plane flight.  You arrive at Heathrow and accidentally picked up several bags belonging to an elderly pensioner.  Nothing in the pensioners’ bags seem to be of use and if you wore any of the clothing contained in the bag would make other people look at you a little oddly.  This extra luggage is very similar to what psychologists call ‘comorbidities’.  Comorbidities are additional diagnosis on top of the major diagnosis you are given.  In addition to the main mental health issue that you have (e.g. OCD – obsessive compulsive disorder) other small and unwanted issues come along for the ride.  These bags are not as big as the luggage you normally travel with but the extra issues can weigh you down.

Anxiety and depression are common with OCD but a symptoms of autism spectrum disorder and attention deficit/hyperactivity disorder also can hang on as extra luggage (comorbidities).  Researcher Gideon Anholt and co-workers believe that OCD, ASD (Autism Spectrum Disorder) and ADHD (Attention Deficit Hyperactivity Disorder) can appear together because they present associated symptoms due to a common dysfunction in the brain.  Specifically in the basal ganglia. The basal ganglia is located in the middle of the brain roughly at eye level.  My interpretation of the paper is that depending on the type of dysfunction of the basal ganglia you get a mix of symptoms that are recognised as symptoms of ASD, OCD and ADHD.  The basal ganglia is not the sole brain area responsible for these symptoms but they appear frequently together as they share an underlying set of causes. For OCD in particular an inability to manage attention switching may lead to memory formation that is untrusted.  Untrusted memories are believed to be responsible for some of the OCD symptoms such as checking behaviours (e.g. door locks, oven and fridge doors).

The researchers suggest that drugs such as Ritalin could aid in OCD treatment if attention switching issues are further demonstrated to underpin some of the symptoms of OCD.

 

Journal article:

Anholt, G.E., Cath, D.C., Oppen, P.V., Eikelenboom, M.J., Smit, J.H., Megen, H.J., & Balkom, A.J. (2010). Autism and ADHD Symptoms in Patients with OCD: Are They Associated with Specific OC Symptom Dimensions or OC Symptom Severity? Journal of autism and developmental disorders.

Image attribution: http://www.imagecreator.co.uk/

Modified image

Default mode network

OCD is associated with altered connectivity within the default mode network (DMN).  This is a group of brain structures that are hypothesised to work together to perform specific functions.  These include:

  • Self-referential mental activity (Gusnard et al. 2001)
  • Extracting episodic memory (Cabeza et al. 2002)
  • Imagining the future (Schacter et al. 2007)
  • Mind wandering (Mason et al. 2007)

The default mode network are highlighted in orange below.

Default mode network

Chinese researchers (Peng et al) found OCD patients exhibited reduced strength of the default network functional connectivity with the posterior cingulate cortex (PCC), and increased functional connectivity in the right inferior frontal lobe, insula, superior parietal cortex and superior temporal cortex.

A small study of people with OCD and siblings indicated a genetic basis for OCD symptoms via the actions of the default mode network.

 

Journal reference:

Peng, Z., Xu, T., He, Q., Shi, C., Wei, Z., Miao, G., . . . Chan, R. (2014). Default network connectivity as a vulnerability marker for obsessive compulsive disorder. Psychological Medicine, 44(7), 1475-1484. doi:10.1017/S0033291713002250

 

Image attribution:

By John Graner, Neuroimaging Department, National Intrepid Center of Excellence, Walter Reed National Military Medical Center, 8901 Wisconsin Avenue, Bethesda, MD 20889, USA. – http://www.frontiersin.org/Neurotrauma/10.3389/fneur.2013.00016/full, Public Domain, https://commons.wikimedia.org/w/index.php?curid=25872800

Problem with your glutamatergic neurotransmission?

The part of the brain that is the hub of emotions is the limbic system.  It is hidden roughly in the centre of the brain.  The amygdala and the hippocampus are two of the most well-known structures. Sitting at the top of this area is the cingulate cortex. It is shown in red in the diagram above. It looks a little like a fat worm.  Unlike a worm this region of the brain have neurons that connect above and below into crucial elements of the limbic system.  The ACC not only process information but passes it into and out of the limbic system. The whole limbic area is significant for the experience of anxiety.  For researchers interested in OCD the cingulate cortex is particularly of interest.  Specifically, the section towards the front (anterior cingulate cortex) shows abnormal activity compared to people without OCD.

In 2015 Massachusetts researchers Brian Brennan and others examined the anterior cingulate cortex (ACC).  They identified that the front tip of the ACC (rostral subdivision) experienced abnormal activity of neurotransmitters.  Neurotransmitters provide a chemical mechanism to send signal between neurons.  In overly simplistic terms the neurotransmitters are chemicals that connect two special brain cells (neurons) in the same way that a pool of water would help conduct electricity between two live wires.  Specifically abnormal glutamatergic neurotransmission has been repeatedly found by a number of researchers to be a problem in this area of the brain. This study specifically identified that the glutamine to glutamate ratio was different between healthy and OCD individuals in the ACC.  There are genes that help control these glutamatergic neurotransmitters and we will discover in later posts that these faulty genes for poor glutamatergic balance can be found in OCD suffers.  It is no doubt overly simplistic but there is at least a plausible hypothesis to the inheritance and the expression of OCD using this pathway.

A key element of the study shows that deactivation of the rostral area of the ACC (rACC) is specific to OCD-related stimuli and was not present in emotional salient stimuli unrelated to OCD.  That is an image of germs will more likely trigger the observed abnormal neurotransmitter issue than a picture of a cute cat.  The researchers conclude that there is an inability to disengage attention from emotional and OCD related stimulus reducing the persons capacity at a cognitive task.  That is the brain stays fixated on the fear for much longer and problem solving capabilities nosedive.  Brian Brennan suggested that the fear centre (amygdala) becomes excited by an emotional OCD stimulus and the tip of the anterior cingulate cortex fails to dampen down the amygdala’s excitement.  This would result in an inability to focus rationally on the stimulus and leave a heightened sense of fear.  A sensation experienced by individuals with OCD.

 

References:

An Examination of Rostral Anterior Cingulate Cortex Function and Neurochemistry in Obsessive–Compulsive Disorder

Neuropsychopharmacology (2015) 40, 1866–1876  © 2015 American College of Neuropsychopharmacology. All rights reserved 0893-133X/15



Image attribution:

By see below (see below) [CC BY-SA 2.1 jp (https://creativecommons.org/licenses/by-sa/2.1/jp/deed.en)], via Wikimedia Commons



Disclaimer:

This content is not intended to provide medical or mental health advice.  It is intended to stimulate an increased understanding of OCD.  The content may not be accurate or express the views of the journal article authors.

Slow road to OCD

There are people who can balance very large stones on top of each other.  It is a very unnatural sculpture that looks as if it about to fall. The TV presenter Kevin McCloud had a go at it.  He stated the blindly obvious, that it was not an easy thing to do.  This delicately balanced pile of stones can be a metaphor for how the brain works.  Everything in the right place processing and transferring data at the right speed.

The brain is made up of irregular shaped clumps of cells called neurons that often have a special function.  These clumps of neurons have been given special names and some of these will be discussed later.  These specialised areas may interpret sensory data, move data to other parts of the brain or construct meaning.

For people with OCD the way the sensory data is transformed into meaning is of particular interest.  Unless the brain is experiencing something as dramatic as schizophrenia this constructed meaning is generally construed as reality.  That is a reality that is communally shared.   But what if distorted reality is not as dramatic as schizophrenia.  What if there is just a slight tilt to the right. A small tilt due to a tiny imbalance within the brain.

What we do know is that people with OCD have different levels of connectivity to certain parts of the brain.  This means traffic between selected parts of the brain flow more often in some places and less in others.

Currently there is a six-lane highway from Brisbane to the Gold Coast that is filled with cars ferrying people and goods all day and all night.  At each end of the highway the cities are growing faster than if there was only a two-lane road.  The people at the Gold Coast end spend their time building bigger and better shopping centres with more and more palm trees.  At the Brisbane end we have the cultural icons of GOMA and leading edge theatre.  Each city has its specialisation because of the traffic that flows into each city.  The brain operates in a similar manner and if the flow of traffic into the specialised area is significantly changed then the output from the brain will also change.

For people with OCD the key area of the brain that has traffic flow problems is called the default mode network.  It is a group of neurons that is used in daydreaming, memory, thoughts about yourself, mind wandering and contemplating the future.  It is easy to imagine how malfunctions in this area might construct distorted thinking patterns.  The technical summary can be found here. People with OCD demonstrated traffic flow and processing activity problems.  That is under and over activity.  Similar brain patterns were found in the close family members even if they did not have a clinical diagnosis of OCD.  This is a strong indicator that genetics is responsible for how OCD achieves its distorted reality.

OCD is reflected in the physical connectivity of the brain.  Even if you don’t have OCD your genetic background has conspired to create a fertile soil where reality can be much more easily distorted.

The default mode network is a target area for treatment for OCD.  Here is an new research article on how deep brain stimulation is used to address treatment resistant OCD.

 

 

Default network connectivity as a vulnerability marker for obsessive compulsive disorder.

Z.W. Peng, T. Xu, Q.H. He, C. Z. Shi, Z. Wei, G.D. Miao, J. Jing, K.O. Lim, X.N. Zuo,

and R. C. K. Chan.

Psychological Medicine (2014), 44, 1475–1484. © Cambridge University Press 2013

doi:10.1017/S0033291713002250



Image attribution:

By User Minesweeper on en.wikipedia - Minesweeper, CC BY-SA 3.0, https://commons.wikimedia.org/w/index.php?curid=1302402
By Leandro Inocencio - Own work, CC BY-SA 3.0, https://commons.wikimedia.org/w/index.php?curid=22166102
Disclaimer: This content is not intended to provide medical or mental health advice.  It is intended to stimulate an increased understanding of OCD.  The content may not be accurate or express the views of the journal article authors.